Interaction of chikungunya virus glycoproteins with macrophage factors controls virion production.

Despite their role as innate sentinels, macrophages can serve as cellular reservoirs of chikungunya virus (CHIKV), a highly-pathogenic arthropod-borne alphavirus that has caused large outbreaks among human populations. Here, with the use of viral chimeras and evolutionary selection analysis, we define CHIKV glycoproteins E1 and E2 as critical for virion production in THP-1 derived human macrophages. Through proteomic analysis and functional validation, we further identify signal peptidase complex subunit 3 (SPCS3) and eukaryotic translation initiation factor 3 subunit K (eIF3k) as E1-binding host proteins with anti-CHIKV activities. We find that E1 residue V220, which has undergone positive selection, is indispensable for CHIKV production in macrophages, as its mutation attenuates E1 interaction with the host restriction factors SPCS3 and eIF3k. Finally, we show that the antiviral activity of eIF3k is translation-independent, and that CHIKV infection promotes eIF3k translocation from the nucleus to the cytoplasm, where it associates with SPCS3. These functions of CHIKV glycoproteins late in the viral life cycle provide a new example of an intracellular evolutionary arms race with host restriction factors, as well as potential targets for therapeutic intervention.

Adherence to non-pharmaceutical interventions following COVID-19 vaccination: a federated cohort study.

In pandemic mitigation, strategies such as social distancing and mask-wearing are vital to prevent disease resurgence. Yet, monitoring adherence is challenging, as individuals might be reluctant to share behavioral data with public health authorities. To address this challenge and demonstrate a framework for conducting observational research with sensitive data in a privacy-conscious manner, we employ a privacy-centric epidemiological study design: the federated cohort. This approach leverages recent computational advances to allow for distributed participants to contribute to a prospective, observational research study while maintaining full control of their data. We apply this strategy here to explore pandemic intervention adherence patterns. Participants (n = 3808) were enrolled in our federated cohort via the "Google Health Studies" mobile application. Participants completed weekly surveys and contributed empirically measured mobility data from their Android devices between November 2020 to August 2021. Using federated analytics, differential privacy, and secure aggregation, we analyzed data in five 6-week periods, encompassing the pre- and post-vaccination phases. Our results showed that participants largely utilized non-pharmaceutical intervention strategies until they were fully vaccinated against COVID-19, except for individuals without plans to become vaccinated. Furthermore, this project offers a blueprint for conducting a federated cohort study and engaging in privacy-preserving research during a public health emergency.

Laboratory Management of Mammalian Hosts for Ixodes scapularis -Host-Pathogen Interaction Studies.

Due to their hematophagous life cycle, hard-bodied ticks including the genus Ixodes are a potential vector for numerous pathogenic organisms including bacteria, protozoa, viruses, and infectious prions. The natural geographic range of several hard tick species, includig Ixodes scapularis, has expanded over recent decades. Consequently, there is an ongoing need to maintain, feed, and propagate ticks for host-pathogen interaction studies to better understand and mitigate their impact on human and animal health. Artificial membrane feeding of hard ticks has advanced in recent years, has study design advantages, and should be used, when possible, to reduce animal use, but it also has several limitations that require the continued use of mammalian hosts including mice, guinea pigs, and rabbits. In this overview, we discuss the best management practices for these relevant species with respect to biosafety, health, and optimal host comfort when used in studies that depend on tick feeding. The capsule-jacket method is preferred over the ear sock-E-collar method of tick feeding on rabbit hosts because of better host health, comfort, and increased study versatility.

Cardiac Output Directly Influences Intracardiac Air After Venous Air Embolism: An Echocardiographic Model Comparing Position Change on Intracardiac Air Bubble Clearance.

BACKGROUND AND OBJECTIVES: Venous air embolism (VAE) can cause significant morbidity and mortality. Prevention and management of VAE include cessation of air entrainment, positioning changes, and hemodynamic support. The degree to which position change and cardiac output (CO) moderate resolution of intracardiac air has not been rigorously studied using contemporary transesophageal echocardiography (TEE). METHODS: This observational cohort-type study aimed to identify the effect of supine vs sitting positioning on the movement and resolution of intracardiac air. In 20 patients undergoing seated neurosurgery, central venous air aspiration catheters were placed through the median basilic vein. TEE was used to estimate the time required for clearance of agitated microbubbles from the right atrium and ventricle in both the supine and sitting position. Estimates of CO were also obtained echocardiographically in each position. RESULTS: Average clearance time was faster in the sitting vs the supine position with no significant difference in CO. A negative correlation between CO and right atrial clearance time across all patients was demonstrated with a Pearson coefficient of -0.4 (95% CI -0.07, -0.65) with P = .02. CONCLUSION: During VAE, both patient position and CO can significantly affect how bubbles move through intracardiac chambers. However, augmenting CO during VAE may be clinically more feasible, efficient, and productive than changing positioning-especially during crises unless the changing in position is intended to halt the entrainment of air. Further TEE studies of intravascular air movement affected by other position changes (lateral, reverse Trendelenburg) and vasopressors should be considered.

RUNX1 interacts with lncRNA SMANTIS to regulate monocytic cell functions.

Monocytes, the circulating macrophage precursors, contribute to diseases like atherosclerosis and asthma. Long non-coding RNAs (lncRNAs) have been shown to modulate the phenotype and inflammatory capacity of monocytes. We previously discovered the lncRNA SMANTIS, which contributes to cellular phenotype expression by controlling BRG1 in mesenchymal cells. Here, we report that SMANTIS is particularly highly expressed in monocytes and lost during differentiation into macrophages. Moreover, different types of myeloid leukemia presented specific SMANTIS expression patterns. Interaction studies revealed that SMANTIS binds RUNX1, a transcription factor frequently mutated in AML, primarily through its Alu-element on the RUNT domain. RNA-seq after CRISPR/Cas9-mediated deletion of SMANTIS or RUNX1 revealed an association with cell adhesion and both limited the monocyte adhesion to endothelial cells. Mechanistically, SMANTIS KO reduced RUNX1 genomic binding and altered the interaction of RUNX1 with EP300 and CBFB. Collectively, SMANTIS interacts with RUNX1 and attenuates monocyte adhesion, which might limit monocyte vascular egress.

Adaptive-Driven CT Simulation-Free Soft Tissue Stereotactic Body Radiation Therapy: A Single-Patient Case Report.

Online adaptive radiotherapy (ART) enables accommodation for variations in patient setup and anatomical changes, allowing for fractional replanning for target coverage, organ at risk (OAR) sparing, and application of CT simulation-free (SF) workflows. SF workflows bypass the conventional simulation CT scan at the potential trade-off in dosimetric uncertainty. ART can alleviate many of these uncertainties, and this work extends previous experience with an Ethos adaptive cone-beam computed tomography (CBCT)-based SF process to treating a unique bony and soft tissue case with stereotactic body radiation therapy (SBRT). The patient is an 83-year-old male with metastatic prostate cancer, presenting with metastases near the right posterior ischium and a right perirectal lymph node. The patient's history includes multiple radiation treatments and androgen deprivation therapy (ADT). Rising prostate-specific antigen(PSA) levels and new metastases identified via positron emission tomography (PET)/CT prostate-specific membrane antigen (PSMA) led to SBRT re-irradiation, considered safe due to the time lapse since previous treatments. Using a HyperSight-equipped Ethos ART system, an SF SBRT workflow utilized the patient's recent PET/CT images for target and OAR delineation. A nine-field adaptive intensity-modulated radiotherapy(IMRT) treatment plan was generated to deliver 3600 Gy in three fractions with a primary focus to limit the dose to proximal OARs and the previously treated region. At the adaptive treatment, the patient is positioned based on anatomical marks, and axial images from HyperSight CBCT are used to contour the OARs and targets. These modified contours accommodate daily variations and are used to recalculate the reference plan and generate a new adapted plan. The adapted plan is selected if coverage improvement and OAR sparing are achieved. For each newly adapted plan, Ethos-generated synthetic CT is reviewed prior to treatment to verify no errors occurred in the deformable propagation between the reference image and the fractional CBCT. For this patient, the adapted plan was selected for all fractions due to improved target coverage, particularly of the soft tissue target, and OAR sparing. The patient tolerated the treatment well and demonstrated a good response on three-month follow-up PSMA PET/CT imaging. This case highlights the efficacy of CBCT-driven SF ART in complex re-irradiation scenario. Future enhancements in the Ethos treatment planning system, including direct dose computation on HyperSight CBCT images, will streamline SF workflows and expand their applicability. Careful consideration of potential on-unit OAR changes and target motion remains crucial for successful SF ART applications.

IGFBP7 is upregulated in islets from T2D donors and reduces insulin secretion.

Intra-islet crosstalk has become a focus area to fully understand the regulation of insulin secretion and impaired ß-cell function in type 2 diabetes (T2D). Here, we put forward evidence for insulin-like growth factor binding protein 7 (IGFBP7) as a potential protein involved in autocrine and paracrine ß-cell regulation. We showed presence of IGFBP7 in granules of both human α- and ß-cells and measured elevated gene expression as well as IGFBP7 protein in T2D. Insulin secretion was reduced in human islets, and the human ß-cell line EndoC-ßH1, after 72-h incubation with IGFBP7. Mechanistically reduced insulin secretion by IGFBP7 is attributed to reduced p21-activated kinase 1 (PAK1) protein, and decreased oxygen consumption and ATP-production. Knockdown of IGFBP7 in EndoC-ßH1 cells verified reduced IGFBP7 levels in the medium, as well as improved insulin secretion. Finally, IGFBP7 knockdown in islets from T2D donors improved insulin secretion, making IGFBP7 a potential drug target in diabetes.

Prevalence of Healthcare Barriers Among US Adults With Chronic Liver Disease Compared to Other Chronic Diseases.

Background and Aims: The extent of healthcare barriers and its association with acute care use among adults with chronic liver disease (CLD) relative to other chronic conditions remains understudied. We compared the probability of barriers and recurrent acute care use among persons with CLD and persons with chronic obstructive pulmonary disease (COPD) and/or cardiovascular disease (CVD). Methods: We assembled a population-based, cross-sectional study using pooled self-reported National Health Interview Survey data (2011-2017) among community-dwelling persons. Probability of barriers by disease group (CLD vs COPD/CVD) was assessed using hurdle negative binomial regression. Results: The sample included 47,037 adults (5062 with CLD, 41,975 with COPD/CVD). The CLD group was younger (median age 55 vs 62 years) and included more Hispanics (17.5% vs 8.6%) and persons with poverty (20.1% vs 15.3%) than the COPD/CVD group. More respondents with CLD vs COPD/CVD reported barriers (44.7% vs 34.4%), including unaffordability (27.5% vs 18.8%), transportation-related (6.1% vs 4.1%), and organizational barriers at entry to (17.6% vs 13.0%) and within healthcare (19.5% vs 14.2%). While adults with CLD were more likely to experience at least 1 barrier (adjusted incident rate ratio, 1.12 [1.01-1.24], P = .03), they were not associated with more (1.05 [1.00-2.71], P = .06). Probability of recurrent acute care use was associated with more healthcare barriers. Conclusion: Findings from this nationally representative sample of over 43 million US adults reveal that persons with CLD have increased probability of healthcare barriers, likely related to their higher prevalence of socioeconomic vulnerabilities compared to persons with COPD/CVD. CLD warrants attention as a priority condition in public policies that direct resources towards high-risk populations.

Disparities in COVID-19 vaccine uptake, attitudes, and experiences between food system and non-food system essential workers.

The COVID-19 pandemic has disproportionately affected the health of food system (FS) essential workers compared with other essential and non-essential workers. Even greater disparity exists for workers in certain FS work settings and for certain FS worker subpopulations. We analyzed essential worker respondents (n = 151,789) in May-November 2021 data from the National Immunization Survey Adult COVID Module (NIS-ACM) to assess and characterize COVID-19 vaccination uptake (≥1 dose) and intent (reachable, reluctant), attitudes about COVID-19 and the vaccine, and experiences and difficulties getting the vaccine. We compared rates, overall and by certain characteristics, between workers of the same group, and between FS (n = 17,414) and non-food system (NFS) worker groups (n = 134,375), to determine if differences exist. FS worker groups were classified as "agriculture, forestry, fishing, or hunting" (AFFH; n = 2,730); "food manufacturing facility" (FMF; n = 3,495); and "food and beverage store" (FBS; n = 11,189). Compared with NFS workers, significantly lower percentages of FS workers reported ≥1 dose of COVID-19 vaccine or vaccine requirements at work or school, but overall vaccine experiences and difficulties among vaccinated FS workers were statistically similar to NFS workers. When we examined intent regarding COVID-19 vaccination among unvaccinated FS workers compared with NFS counterparts, we found a higher percentage of FMF and FBS workers were reachable whereas a higher percentage of AFFH workers were reluctant about vaccination, with differences by sociodemographic characteristics. Overall, results showed differences in uptake, intent, and attitudes between worker groups and by some sociodemographic characteristics. The findings reflect the diversity of FS workers and underscore the importance of collecting occupational data to assess health inequalities and of tailoring efforts to worker groups to improve confidence and uptake of vaccinations for infectious diseases such as COVID-19. The findings can inform future research, adult infectious disease interventions, and emergency management planning.

Cefepime-taniborbactam activity against antimicrobial-resistant clinical isolates of Enterobacterales and Pseudomonas aeruginosa: GEARS global surveillance programme 2018-22.

OBJECTIVES: Taniborbactam is a boronate-based ß-lactamase inhibitor in clinical development in combination with cefepime. METHODS: Cefepime-taniborbactam and comparator broth microdilution MICs were determined for patient isolates of Enterobacterales (n = 20 725) and Pseudomonas aeruginosa (n = 7919) collected in 59 countries from 2018 to 2022. Taniborbactam was tested at a fixed concentration of 4 mg/L. Isolates with cefepime-taniborbactam MICs ≥ 16 mg/L underwent WGS. ß-Lactamase genes were identified in additional meropenem-resistant isolates by PCR/Sanger sequencing. RESULTS: Taniborbactam reduced the cefepime MIC90 value for all Enterobacterales from >16 to 0.25 mg/L (>64-fold). At ≤16 mg/L, cefepime-taniborbactam inhibited 99.5% of all Enterobacterales isolates; >95% of isolates with MDR and ceftolozane-tazobactam-resistant phenotypes;  ≥ 89% of isolates with meropenem-resistant and difficult-to-treat-resistant (DTR) phenotypes; >80% of isolates with meropenem-vaborbactam-resistant and ceftazidime-avibactam-resistant phenotypes; 100% of KPC-positive, 99% of OXA-48-like-positive, 99% of ESBL-positive, 97% of acquired AmpC-positive, 95% of VIM-positive and 76% of NDM-positive isolates. Against P. aeruginosa, taniborbactam reduced the cefepime MIC90 value from 32 to 8 mg/L (4-fold). At ≤16 mg/L, cefepime-taniborbactam inhibited 96.5% of all P. aeruginosa isolates; 85% of meropenem-resistant phenotype isolates; 80% of isolates with MDR and meropenem-vaborbactam-resistant phenotypes; >70% of isolates with DTR, ceftazidime-avibactam-resistant and ceftolozane-tazobactam-resistant phenotypes; and 82% of VIM-positive isolates. Multiple potential mechanisms of resistance, including carriage of IMP, or alterations in PBP3 (ftsI), porins (decreased permeability) and efflux (up-regulation) were present in most isolates with cefepime-taniborbactam MICs ≥ 16 mg/L. CONCLUSIONS: Cefepime-taniborbactam exhibited potent in vitro activity against Enterobacterales and P. aeruginosa, and inhibited most carbapenem-resistant isolates, including those carrying serine carbapenemases or NDM/VIM MBLs.

Multi-trait and multi-ancestry genetic analysis of comorbid lung diseases and traits improves genetic discovery and polygenic risk prediction.

While respiratory diseases such as COPD and asthma share many risk factors, most studies investigate them in insolation and in predominantly European ancestry populations. Here, we conducted the most powerful multi-trait and -ancestry genetic analysis of respiratory diseases and auxiliary traits to date. Our approach improves the power of genetic discovery across traits and ancestries, identifying 44 novel loci associated with lung function in individuals of East Asian ancestry. Using these results, we developed PRSxtra (cross TRait and Ancestry), a multi-trait and -ancestry polygenic risk score approach that leverages shared components of heritable risk via pleiotropic effects. PRSxtra significantly improved the prediction of asthma, COPD, and lung cancer compared to trait- and ancestry-matched PRS in a multi-ancestry cohort from the All of Us Research Program, especially in diverse populations. PRSxtra identified individuals in the top decile with over four-fold odds of asthma and COPD compared to the first decile. Our results present a new framework for multi-trait and -ancestry studies of respiratory diseases to improve genetic discovery and polygenic prediction.

Effect of different modalities of exercise on Fatty Liver Index in patients with metabolic syndrome: The RESOLVE randomized trial.

INTRODUCTION: Metabolic associated liver disease (MASLD) is the most common liver disease in the world especially in people with metabolic syndrome. First-line treatments mainly consist in lifestyle modifications for these populations. The main objective of this study is to assess the effect of a short intervention program with different exercise modalities on Fatty Liver Index (FLI) in patients with metabolic syndrome. METHODS: 85 patients (40 men, 45 women) with metabolic syndrome and liver steatosis were randomized in 3 groups for a 3 weeks residential program: Re group-high-resistance-moderate-endurance; rE group-moderate-resistance with high-endurance and re group-moderate-resistance with moderate-endurance. Patients also followed a negative energy balance of 500 kcal/day. Then, a follow-up of 1 year with interviews with dieticians and exercise physicians to maintain lifestyle modification was performed. Anthropometric, cardiometabolic and hepatic outcomes were performed at baseline, at the end of the 3-week residential program, 3 months, 6 months and 12 months after baseline. RESULTS: This study demonstrated that all three training programs significantly improve FLI and that this effect was lasting among the follow-up (p < 0.001). More specifically, the Re group exhibited a more pronounced decrease in FLI compared with re (p < 0.05). Finally, the decrease in FLI was associated with improvement in anthropometric and cardiometabolic outcomes at 3-weeks (p < 0.001) and 3-months (p < 0.01). CONCLUSION: Short duration program is effective to improve FLI and cardiometabolic parameters in MASLD patients. Encourage to increase physical activity even for a short duration is relevant in this population.

Measuring episodic memory and mental time travel: crossing the species gap.

Mental time travel is the projection of the mind into the past or future, and relates to experiential aspects of episodic memory, and episodic future thinking. Framing episodic memory and future thinking in this way causes a challenge when studying memory in animals, where demonstration of this mental projection is prevented by the absence of language. However, there is good evidence that non-human animals pass tests of episodic memory that are based on behavioural criteria, meaning a better understanding needs to be had of the relationship between episodic memory and mental time travel. We argue that mental time travel and episodic memory are not synonymous, and that mental time travel is neither a requirement of, nor an irrelevance to, episodic memory. Mental time travel can allow improved behavioural choices based on episodic memory, and work in all species (including humans) should include careful consideration of the behavioural outputs being measured. This article is part of the theme issue 'Elements of episodic memory: lessons from 40 years of research'.

Complete Genome of Achromobacter xylosoxidans, a Nitrogen-Fixing Bacteria from the Rhizosphere of Cowpea (Vigna unguiculata [L.] Walp) Tolerant to Cucumber Mosaic Virus Infection.

Achromobacter xylosoxidans is one of the nitrogen-fixing bacteria associated with cowpea rhizosphere across Africa. Although its role in improving soil fertility and inducing systemic resistance in plants against pathogens has been documented, there is limited information on its complete genomic characteristics from cowpea roots. Here, we report the complete genome sequence of A. xylosoxidans strain DDA01 isolated from the topsoil of a field where cowpea plants tolerant to cucumber mosaic virus (CMV) were grown in Ibadan, Nigeria. The genome of DDA01 was sequenced via Illumina MiSeq and contained 6,930,067 nucleotides with 67.55% G + C content, 73 RNAs, 59 tRNAs, and 6421 protein-coding genes, including those associated with nitrogen fixation, phosphate solubilization, Indole3-acetic acid production, and siderophore activity. Eleven genetic clusters for secondary metabolites, including alcaligin, were identified. The potential of DDA01 as a plant growth-promoting bacteria with genetic capabilities to enhance soil fertility for resilience against CMV infection in cowpea is discussed. To our knowledge, this is the first complete genome of diazotrophic bacteria obtained from cowpea rhizosphere in sub-Saharan Africa, with potential implications for improved soil fertility, plant disease resistance, and food security.

Capsule release surgery temporarily reduces contracture in a rat elbow model of arthrofibrosis.

Elbow trauma can lead to joint contracture and reduced range of motion (ROM). Nonsurgical interventions can improve ROM, but in some cases capsule release surgery is required. Although surgery can improve ROM, it often does not restore full ROM. Thus, alternatives are needed. One approach is to target activated myofibroblasts, which are commonly associated with fibrotic tissue. Mechanical and biochemical cues drive a feedback loop that can result in normal or pathological healing. We hypothesize that this feedback loop exists in joint contracture and can be manipulated so that myofibroblast activity is reduced, normal healing is achieved, and ROM is improved. We previously demonstrated that blebbistatin can inhibit myofibroblast contractile forces and reduce collagen synthesis in vitro. Thus, the purpose of this study was to assess the use of blebbistatin in an animal model of elbow contracture, which was induced in 7 groups of 4 rats each (n = 28). All elbows were mechanically and histologically tested. The uninjured contralateral elbows of each rat were used as a control group. Capsule release surgery significantly improved (p < 0.01) outcomes 1 week after surgery compared to injury alone and was not significantly different from uninjured elbows. Three weeks after surgery, outcomes worsened, indicating joint stiffening consistent with what is observed clinically. The addition of blebbistatin did not significantly improve outcomes. Future work will investigate relationships among treatment, fibrotic tissue deposition, myofibroblast activity, and biomechanics to determine if blebbistatin is a useful adjunctive therapy for treating joint contracture.

Activation induces shift in nutrient utilization that differentially impacts cell functions in human neutrophils.

Neutrophils utilize a variety of metabolic sources to support their crucial functions as the first responders in innate immunity. Here, through in vivo and ex vivo isotopic tracing, we examined the contributions of different nutrients to neutrophil metabolism under specific conditions. Human peripheral blood neutrophils, in contrast to a neutrophil-like cell line, rely on glycogen storage as a major metabolic source under resting state but rapidly switch to primarily using extracellular glucose upon activation with various stimuli. This shift is driven by a substantial increase in glucose uptake, enabled by rapidly increased GLUT1 on cell membrane, that dominates the simultaneous increase in gross glycogen cycling capacity. Shifts in nutrient utilization impact neutrophil functions in a function-specific manner: oxidative burst depends on glucose utilization, whereas NETosis and phagocytosis can be flexibly supported by either glucose or glycogen, and neutrophil migration and fungal control are enhanced by the shift from glycogen utilization to glucose utilization. This work provides a quantitative and dynamic understanding of fundamental features in neutrophil metabolism and elucidates how metabolic remodeling shapes neutrophil functions, which has broad health relevance.

Effect of RapidShockTM Implementation on Perishock Pause in Out-of-Hospital Cardiac Arrest.

OBJECTIVES: Shorter pauses in cardiopulmonary resuscitation (CPR) are associated with better health outcomes after out-of-hospital cardiac arrest (OHCA). Our primary objective was to examine the effect of a RapidShockTM defibrillator software upgrade compared with standard defibrillator software on the length of perishock pause during care for OHCA among adults. Secondary objectives were to assess the effects of RapidShockTM on other CPR pauses. METHODS: We conducted a retrospective cohort study between September 1, 2015 and September 30, 2020. "Standard" cardiac defibrillator software in manual interpretation mode was used for CPR delivered on or before November 30, 2018, while "RapidShockTM" software (ZOLL® Medical Corporation) was used after this date. For each study group, we calculated the perishock, perianalysis, and total CPR pause; each CPR cycle was considered an independent event. We then calculated the median and interquartile range (IQR) for observed pauses with the "Standard" and "RapidShockTM" software. Percent change in median perishock pause (shockable rhythms), perianalysis pause (non-shockable rhythms), and total CPR pause were compared between CPR administered with each software using the Mann-Whitney test. RESULTS: There were 733 and 782 distinct CPR cycles administered using "Standard" and "RapidShockTM" software, respectively. A 31.8% reduction in median perishock pause was observed with "RapidShockTM" software compared with the "Standard" software (22.0 s (IQR 18.0 - 27.0 s) vs. 15.0 s (IQR 13.0 - 19.0 s); p < 0.01). The decrease in median perishock pause was driven by a reduction in the preshock phase (18 s vs. 10 s; 44.4% decrease in median pause; p < 0.01). No differences were observed in median perianalysis pause between the two groups. When combining shockable and non-shockable rhythms, we observed a reduction of 23.5% in median CPR pause (17.0 s (IQR 11.0 - 24.0 s) vs. 13s (IQR 10.0 - 17.0 s); p < 0.01). CONCLUSIONS: Overall, we observed that the use of "RapidShockTM" defibrillator software was associated with shorter CPR pauses compared with the "Standard" software. Additional studies are required to examine whether further reductions in CPR pauses may be achieved and to investigate associations between shorter CPR pauses and health outcomes.

Data-Driven Implementation Strategy to Optimise Clinician Behaviour Change at Scale in Complex Clinical Environments: A Multicentre Emergency Care Study.

AIM: To develop an evidence-driven, behaviour change focused strategy to maximise implementation and uptake of HIRAID (History including Infection risk, Red flags, Assessment, Interventions, Diagnostics, communication and reassessment) in 30 Australian rural, regional and metropolitan emergency departments. DESIGN: An embedded, mixed-methods study. METHODS: This study is the first phase of a step-wedge cluster randomised control trial of HIRAID involving over 1300 emergency nurses. Concurrent quantitative and qualitative data were collected via an electronic survey sent to all nurses to identify preliminary barriers and enablers to HIRAID implementation. The survey was informed by the Theoretical Domains Framework, which is a synthesis of behavioural change theories that applies the science of intervention implementation in health care to effect change. Quantitative data were analysed using descriptive statistics and qualitative data with inductive content analysis. Data were then integrated to generate barriers and enablers to HIRAID implementation which were mapped to the Theoretical Domains Framework. Corresponding intervention functions and Behaviour Change techniques were selected and an overarching implementation strategy was developed through stakeholder consultation and application of the APEASE criteria (Affordability, Practicability, Effectiveness and cost-effectiveness, Acceptability, Side-effects/safety and Equity). RESULTS: Six barriers to HIRAID implementation were identified by 670 respondents (response rate ~58%) representing all 30 sites: (i) lack of knowledge about HIRAID; (ii) high workload, (iii) lack of belief anything would change; (iv) not suitable for workplace; (v), uncertainty about what to do and (vi) lack of support or time for education. The three enablers were as follows: (i) willingness to learn and adopt something new; (ii) recognition of the need for something new and (iii) wanting to do what is best for patient care. The 10 corresponding domains were mapped to seven intervention functions, 21 behaviour change techniques and 45 mechanisms. The major components of the implementation strategy were a scaffolded education programme, clinical support and environmental modifications. CONCLUSIONS: A systematic process guided by the behaviour change wheel resulted in the generation of a multifaceted implementation strategy to implement HIRAID across rural, regional and metropolitan emergency departments. Implementation fidelity, reach and impact now require evaluation. IMPACT: HIRAID emergency nursing assessment framework reduced clinical deterioration relating to emergency care and improved self-confidence and documentation in emergency departments in pilot studies. Successful implementation of any intervention in the emergency department is notoriously difficult due to workload unpredictability, the undifferentiated nature of patients and high staff turnover. Key barriers and enablers were identified, and a successful implementation strategy was developed. This study uses theoretical frameworks to identify barriers and enablers to develop a data-driven, behavioural-focused implementation strategy to optimise the uptake of HIRAID in geographically diverse emergency departments which can be used to inform future implementation efforts involving emergency nurses. REPORTING METHOD: The CROSS reporting method (Supporting Information S3) was used to adhere to EQUATOR guidelines. PATIENT OR PUBLIC CONTRIBUTION: No Patient or Public Contribution. TRIAL REGISTRATION: Australian New Zealand; Clinical Trials Registry (ANZCTR) number: ACTRN12621001456842, registered 25/10/2021.

VHL synthetic lethality screens uncover CBF-ß as a negative regulator of STING.

Clear cell renal cell carcinoma (ccRCC) represents the most common form of kidney cancer and is typified by biallelic inactivation of the von Hippel-Lindau ( VHL ) tumour suppressor gene. Here, we undertake genome-wide CRISPR/Cas9 screening to reveal synthetic lethal interactors of VHL , and uncover that loss of Core Binding Factor ß (CBF-ß) causes cell death in VHL -null ccRCC cell lines and impairs tumour establishment and growth in vivo . This synthetic relationship is independent of the elevated activity of hypoxia inducible factors (HIFs) in VHL -null cells, but does involve the RUNX transcription factors that are known binding partners of CBF-ß. Mechanistically, CBF-ß loss leads to upregulation of type I interferon signalling, and we uncover a direct inhibitory role for CBF-ß at the STING locus controlling Interferon Stimulated Gene expression. Targeting CBF-ß in kidney cancer both selectively induces tumour cell lethality and promotes activation of type I interferon signalling.

Putting computational models of immunity to the test - an invited challenge to predict B. pertussis vaccination outcomes.

Systems vaccinology studies have been used to build computational models that predict individual vaccine responses and identify the factors contributing to differences in outcome. Comparing such models is challenging due to variability in study designs. To address this, we established a community resource to compare models predicting B. pertussis booster responses and generate experimental data for the explicit purpose of model evaluation. We here describe our second computational prediction challenge using this resource, where we benchmarked 49 algorithms from 53 scientists. We found that the most successful models stood out in their handling of nonlinearities, reducing large feature sets to representative subsets, and advanced data preprocessing. In contrast, we found that models adopted from literature that were developed to predict vaccine antibody responses in other settings performed poorly, reinforcing the need for purpose-built models. Overall, this demonstrates the value of purpose-generated datasets for rigorous and open model evaluations to identify features that improve the reliability and applicability of computational models in vaccine response prediction.